Abstract: TH-PO0538
Defects in Nephrogenesis Result in an Expansion of the Foxd1+ Stromal Progenitor Population
Session Information
- Development, Stem Cells, and Regenerative Medicine
November 06, 2025 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Development, Stem Cells, and Regenerative Medicine
- 600 Development, Stem Cells, and Regenerative Medicine
Authors
- Drake, Keri A., The University of Texas Southwestern Medical Center, Dallas, Texas, United States
- Michalopulos, Michael G., University of Iowa Hospitals and Clinics, Iowa City, Iowa, United States
- Liu, Yan, The University of Texas Southwestern Medical Center, Dallas, Texas, United States
- Ravindraraju, Dinesh, The University of Texas Southwestern Medical Center, Dallas, Texas, United States
- Lafin, John T, The University of Texas Southwestern Medical Center, Dallas, Texas, United States
- Ma, Yanru, The University of Texas Southwestern Medical Center, Dallas, Texas, United States
- Gaur, Dhruv, Midwestern University Chicago College of Osteopathic Medicine, Downers Grove, Illinois, United States
- Khadka, Sadiksha, The University of Texas Southwestern Medical Center, Dallas, Texas, United States
- Xing, Chao, The University of Texas Southwestern Medical Center, Dallas, Texas, United States
- McMahon, Andrew P., California Institute of Technology Division of Biology and Biological Engineering, Pasadena, California, United States
- Carroll, Thomas J., The University of Texas Southwestern Medical Center, Dallas, Texas, United States
Background
Reciprocal signaling interactions coordinate multiple aspects of kidney development. While signals from the stroma have been shown to regulate nephron progenitor cell (NPC) differentiation, much less is known about how the stromal progenitor population is regulated. Here we sought to use in-vivo mouse models disrupting the NPC lineage to investigate how defects in nephrogenesis may non-autonomously affect stromal development, with the overall goal of uncovering additional mechanisms of cell-lineage crosstalk in development and disease.
Methods
Three genetically engineered mouse models were examined, including 1) Six2cre;Wt1c/c mutant kidneys, with Wt1 ablation in the NPCs shown to block NPC differentiation, 2) Wnt4-null mutants, which also fail to undergo NPC differentiation but without targeting the self-renewing NPC population as in the Six2cre;Wt1c/c model, and 3) NPC ablation via diphtheria toxin via Six2cre;RosaDTAc/+. Single nuclei RNA-seq (snRNA-seq) provided additional profiling of the Foxd1+ stromal progenitor cells in murine kidneys, which was further evaluated in human fetal kidneys and Wilms tumor samples.
Results
In all three mutant models, an expansion of the nephrogenic zone stroma was confirmed by immunoassays and in-situ hybridization, demonstrating that defects in nephrogenesis result in an accumulation of the Foxd1+ stromal progenitor population. Additional analyses of control and mutant murine kidneys identified a distinct subcluster of the Foxd1+ stroma, with snRNA-seq suggesting that this subpopulation is conserved in human fetal kidneys and shows transcriptional similarities to the majority of stroma from human Wilms tumor samples, supporting the hypothesis that embryonal tumor stroma maintains a “progenitor-like” phenotype.
Conclusion
Overall, this study demonstrates that murine models with defects in NPC differentiation result in an abnormal expansion of stromal progenitor cells, further highlighting roles of cell-lineage crosstalk in normal development and its potential to contribute to developmentally related kidney disease, such as Wilms tumor.
Funding
- NIDDK Support